Merkel cell carcinoma (MCC) is a rare neuroendocrine skin tumor with a poor prognosis at advanced disease stages due to the unavailability of effective treatments. Most MCCs carry sequences from a novel polyomavirus, Merkel cell polyomavirus (MCPyV), and express two putative oncoproteins: MCPyV small t antigen (stAg) and tumor-specific truncated large T antigen (tLTAg). Like other viral oncoproteins, MCPyV transforming antigens target endogenous proteins that function as tumor suppressors: tLTAg targets RB1 while stAg targets PP2A and Fbw7, a component of the SCF ubiquitin ligase complex. Loss-of-function studies point to an important role for both tLTAg and stAg in MCC. Gain-of-function studies, on the other hand, show that stAg, but neither tLTAg nor full-length LTAg, has transforming potential in cultured cells. This stAg-driven transformation involves 4E-BP1 phosphorylation and resultant de-repression of cap-dependent translation, and is dependent on a novel stAg functional domain that binds Fbw7. The relevance of these in vitro findings to MCC tumor initiation, expansion, and progression, is currently unknown. More specifically, the role of MCPyV T antigens as oncogenic drivers of tumor development in vivo has not been addressed. In this exploratory grant application, we plan to develop and characterize mouse models testing the in vivo response of skin cells to expression of MCPyV st and LTAgs using both conventional and Cre-inducible transgenic mice. The proposed studies are highly significant since they will help fill a critical gap in our knowledge by defining the biological activity of MCPyV TAgs in intact animals, thus providing a much-needed set of tools for studying factors contributing to the development and maintenance of MCC. In addition, these exploratory studies will set the stage for identification of MCPyV TAg cellular targets whose deregulation via non-viral mechanisms may contribute more generally to cancer development. The proposed work is likely to have direct translational relevance to MCC patients as it may lead to the identification of new therapeutic targets and yield much-needed mouse models for functional assays and preclinical trials.